14-22478914-C-T

Variant names:

• chr14-22478914-C-T
• rs1872159
• ENST00000390482.1:c.41C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000390482.1(TRAJ57):​c.41C>T​(p.Thr14Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 762,968 control chromosomes in the GnomAD database, including 9,944 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1401 hom., cov: 26)
  • Exomes 𝑓: 0.14 (8543 hom.)
• Consequence: TRAJ57 ENST00000390482.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63
• Publications: 12 publications found

Genes affected

TRAJ57 (HGNC:12089): (T cell receptor alpha joining 57) T cell receptors recognize foreign antigens which have been processed as small peptides and bound to major histocompatibility complex (MHC) molecules at the surface of antigen presenting cells (APC). Each T cell receptor is a dimer consisting of one alpha and one beta chain or one delta and one gamma chain. In a single cell, the T cell receptor loci are rearranged and expressed in the order delta, gamma, beta, and alpha. If both delta and gamma rearrangements produce functional chains, the cell expresses delta and gamma. If not, the cell proceeds to rearrange the beta and alpha loci. This region represents the germline organization of the T cell receptor alpha and delta loci. Both the alpha and delta loci include V (variable), J (joining), and C (constant) segments and the delta locus also includes diversity (D) segments. The delta locus is situated within the alpha locus, between the alpha V and J segments. During T cell development, the delta chain is synthesized by a recombination event at the DNA level joining a D segment with a J segment; a V segment is then joined to the D-J gene. The alpha chain is synthesized by recombination joining a single V segment with a J segment. For both chains, the C segment is later joined by splicing at the RNA level. Recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random additional of nucleotides by terminal deoxynucleotidyltransferase. Five variable segments can be used in either alpha or delta chains and are described by TRAV/DV symbols. Several V and J segments of the alpha locus are known to be incapable of encoding a protein and are considered pseudogenes. [provided by RefSeq, Aug 2016]

TRA (HGNC:12027):

TRD-AS1 (HGNC:56197): (TRD antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000390482.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRD-AS1	NR_148361.1		n.225+2327G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAJ57	ENST00000390482.1	TSL:6	c.41C>T	p.Thr14Met	missense	Exon 1 of 1	ENSP00000452248.1
	TRD-AS1	ENST00000514473.2	TSL:2	n.225+2327G>A		intron	N/A
	TRD-AS1	ENST00000556777.2	TSL:3	n.562+2327G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16209 AN: 150770 Hom.: 1399 Cov.: 26

Gnomad AFR AF: 0.0466

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0728

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0920

GnomAD2 exomes AF: 0.143 AC: 33266 AN: 232838 AF XY: 0.147

Gnomad AFR exome AF: 0.0474

Gnomad AMR exome AF: 0.0657

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.491

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.140 AC: 85660 AN: 612080 Hom.: 8543 Cov.: 0 AF XY: 0.143 AC XY: 47733 AN XY: 334480

African (AFR) AF: 0.0495 AC: 874 AN: 17662

American (AMR) AF: 0.0666 AC: 2901 AN: 43584

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2125 AN: 20934

East Asian (EAS) AF: 0.445 AC: 16002 AN: 35976

South Asian (SAS) AF: 0.206 AC: 14254 AN: 69304

European-Finnish (FIN) AF: 0.174 AC: 6728 AN: 38662

Middle Eastern (MID) AF: 0.0964 AC: 399 AN: 4140

European-Non Finnish (NFE) AF: 0.109 AC: 38122 AN: 348928

Other (OTH) AF: 0.129 AC: 4255 AN: 32890

GnomAD4 genome AF: 0.107 AC: 16200 AN: 150888 Hom.: 1401 Cov.: 26 AF XY: 0.113 AC XY: 8292 AN XY: 73656

African (AFR) AF: 0.0466 AC: 1909 AN: 40986

American (AMR) AF: 0.0727 AC: 1099 AN: 15110

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 346 AN: 3460

East Asian (EAS) AF: 0.478 AC: 2453 AN: 5134

South Asian (SAS) AF: 0.223 AC: 1065 AN: 4768

European-Finnish (FIN) AF: 0.170 AC: 1762 AN: 10376

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7242 AN: 67766

Other (OTH) AF: 0.0920 AC: 192 AN: 2088

Alfa AF: 0.105 Hom.: 2622

Bravo AF: 0.0956

Asia WGS AF: 0.311 AC: 1084 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.87
PhyloP100		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1872159; hg19: chr14-22947903; COSMIC: COSV66606336;